C. trachomatis is a gram-negative bacterium with an obligate intracellular developmental cycle. Sexually transmitted infections (STI) with Chlamydia trachomatis are common in the US, with approximately 3 million cases occurring annually and a 5% incidence in the adolescent population. Chlamydial STIs primarily cause local infections confined to epithelial cells in the female reproductive tract. However, C. trachomatis infections can also ascend to the upper genital tract (UGT) and induce an inflammatory response, leading to variety of complications that are associated with increased morbidity and reproductive dysfunction, including infertility. Antibiotic administration through screening programs can lower infection rates but may actually increase postinfection complications in females (Brunham et al., J. Infect. Dis., 192:1836-44 (2005)). Hence, a vaccine protecting against C. trachomatis infection would be highly desirable.
CD4+ T-cells expressing the αβ+ T-cell receptor (TCRαβ+) dominate the local lymphocytic infiltrate of patients infected with C. trachomatis (Morrison et al., Infect. Immun., 68(5):2870-9 (2000); Kelly et al., Infect. Immun., 65:5198-208 (1997)) and are necessary for the resolution of Chlamydia genital infection (Cotter et al., Infect. Immun., 65(6):2145-52 (1997); Perry et al., J Immunol., 158:3344-52 (1997); Morrison et al., Infect. Immun., 63(12):4661-8 (1995)). Resolution is dependent on the secretion of gamma interferon (IFNγ) (Perry et al., J. Immunol., 158:3344-52 (1997); Hawkins et al., Infect. Immun., 70(9):5132-9 (2000); Igietseme et al., Regional Immunol., 5:317-24 (1993)) and can be mediated by transferring IFNγ-secreting CD4+ T cells (Th1 cells) to infected subjects (Hawkins et al., Infect. Immun., 70(9):5132-9 (2000); Murthy et al., Infect. Immun., 75(2):666-76 (2007)). In addition, antibody responses can enhance cell-mediated immune protection against C. trachomatis genital infection (Morrison et al., J. Immunol., 175(11):7536-42 (2005)). Thus, a vaccine against C. trachomatis would preferably elicit both a Th1 cell-mediated response and an antibody response against C. trachomatis in the reproductive mucosa while minimizing inflammation associated with C. trachomatis infection.
The Chlamydial protein most studied as a candidate antigen for a Chlamydia vaccine is the Chlamydial major outer membrane protein (MOMP), a 40 kDa integral membrane protein which is the predominant Chlamydial surface protein. While other Chlamydial surface proteins are immunogenic, antibodies against such proteins have not been found to be protective (e.g., Zhang et al., Infect. Immun., 57:636-638 (1989)). A common approach for vaccinating against Chlamydial infection is to stimulate the central immune system by parenteral administration of a subunit vaccine (e.g., Macmillan et al., FEMS Immunology & Medical Microbiology, 49(1):46-55 (2007); Ifere et al., J. Microbiol. Immunol. Infect., 40(3):188-200 (2007)). While such conventionally administered vaccines are capable of providing some protection against infertility (Pal et al., Infect. Immun., 73(12):8153-60 (2005)) they are difficult to produce and ineffective in many subjects.
In contrast to parenteral administration, vaccine administration to mucosal tissues induces strong cellular responses at mucosal surfaces (Neutra et al., Nat. Rev. Immunol., 6(2):148-58 (2006)). Moreover, stimulating the inductive site at a mucosal surface produces immune responses at distant mucosal surfaces (Mestecky, J. Clin. Immunol., 7:265-76 (1987)). For example, stimulating inductive immune sites (NALT) in the nasal mucosa (Zuercher et al., J. Immunol., 168(4):1796-803 (2002)) can induce greater antibody levels at vaginal surfaces (Kozlowski et al., J. Immunol., 169(1):566-74 (2002); Staats et al., AIDS Res. Hum. Retroviruses, 13(11):945-52 (1998)). Immunization of the nasal mucosae can also produce cell-mediated responses in the genital tract. For example, intranansal immunization produced a cytotoxic T lymphocyte (CTL) response against HSV-2 in the genital tract and induced long-lasting protection against reinfection (Gallichan et al., J. Infect. Dis., 177(5):1155-61 (1998)). Recently, intranasal immunization with a Chlamydial peptide provided superior protection against infection and reduced hydrosalpinx following Chlamydial infection (Murthy et al., Infect. Immun., 75(2):666-76 (2007); He et al., Immunology, 122(1):28-37 (2007)).
Thus, there is a need in the art for a Chlamydia vaccine which is suitable for administration to the nasal mucosae and capable of inducing both cellular and antibody-based immune responses and providing protective immunity against infection while minimizing inflammation in the subject.